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Motility, digestive and nutritional problems in Esophageal Atresia
Accepted Manuscript Title: Motility, digestive and nutritional problems in Esophageal Atresia Author: Madeleine Gottrand Laurent Michaud Rony Sfeir Frederic Gottrand PII: DOI: Reference:
S1526-0542(15)00142-6 http://dx.doi.org/doi:10.1016/j.prrv.2015.11.005 YPRRV 1103
To appear in:
YPRRV
Received date: Accepted date:
14-10-2015 16-11-2015
Please cite this article as: Gottrand M, Michaud L, Sfeir R, Gottrand F, Motility, digestive and nutritional problems in Esophageal Atresia, Paediatric Respiratory Reviews (2015), http://dx.doi.org/10.1016/j.prrv.2015.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Motility, digestive and nutritional problems in Esophageal Atresia Madeleine Gottrand, Laurent Michaud, Rony Sfeir, Frederic Gottrand
esophagus, Department of Pediatrics, F-59000 Lille, France
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CHU Lille, Univ. Lille, National reference center for congenital malformation of the
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[email protected], [email protected], [email protected]
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Corresponding author: Frederic Gottrand, [email protected]
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Tel : +333 20 44 61 26, Fax + 333 20 44 61 34
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Conflicts of interest: None
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Summary Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a rare congenital malformation. Digestive and nutritional problems remain frequent in children with EA both in early infancy and at long-term follow-up. These patients are at major risk of presenting with gastroesophageal reflux and its complications, such as anastomotic
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strictures. Esophageal dysmotility is constant, and can have important consequences on feeding and nutritional status. Patients with EA need a systematic follow-up with a
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multidisciplinary team.
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Key words Anastomotic stricture Growth Retardation
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Dysphagia Gastro-Esophageal Reflux
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Dysmotility Nutrition
Educational Aims
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Children
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The reader will come to appreciate that:
Digestive and nutritional problems are frequent and interlinked in esophageal
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atresia.
A multidisciplinary approach is needed in esophageal atresia. Esophageal atresia is not only a surgical neonatal problem but has life-long consequences on the digestive and nutritional morbidity.
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Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a rare congenital malformation1,2. The live-birth prevalence of EA is 1.8 per 10 000 births in France3. The prognosis of EA has benefited from advances in medical care, including neonatal and surgical procedures, and has therefore improved significantly over the past three decades. Its survival rate now exceeds 95% and an increasing number of patients reach adulthood2,3. However, digestive/nutritional problems remain frequent in this
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population both in early infancy and at long-term follow-up4.
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Why are digestive, motility and nutritional problems a concern in patients with EA? Gastro-esophageal reflux (GER)
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Patients with EA are at major risk of presenting GER5. Several factors contribute to
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the physiopathology of GER in EA (Table 1).
Anastomotic stricture
Anastomotic stricture (AS) is favoured by important anastomotic tension related to a long-
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gap between the two esophageal pouches, occurrence of a post-operative anastomotic
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leak and GER18.
Dysmotility
Dysmotility is not only a consequence of surgical repair as abnormal innervation is
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present at birth. It involves the Auerbach plexus, ganglion cells, interstitial cells of Cajal (ICC), and both excitatory and inhibitory intramural nerves mostly in the distal esophageal
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segment rather than in the proximal esophagus19–22. Dysmotility is explained by an imbalance of neurotransmitter excretion in nerve cells with decreased expression of neuronal markers, including vasoactive intestinal polypeptide (VIP) and nitric oxide synthase (NOS)19,20.These congenital changes in the innervation may lead to abnormal contraction and relaxation and subsequent dysphagia, GER, and feeding difficulty in children with EA23.
Nutritional problems Dysphagia is one of the main causes of nutritional problems. Causes of dysphagia include esophagitis, GER, eosinophilic esophagitis, dysmotility, anastomotic strictures, esophageal outlet obstruction, aspiration and fear of feeding. Predictors of poor oral intake
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are long gap atresia, CHARGE association, and neurologic abnormalities24. GER and esophagitis have been implicated as causes of feeding difficulties. However, motility abnormalities may contribute to a much greater extent to dysphagia.Anastomotic strictures are another frequent cause of dysphagia and feeding difficulties.
Fundoplication, which can create a functional esophageal outlet obstruction in the context
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of dysmotility, may also cause or aggravate dysphagia and feeding difficulties. This is supported by a study of children receiving a fundoplication, where 4.3% of the cohort
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without EA presented with dysphagia, versus 17% in children with EA25.
Aspiration is an under-recognized cause of feeding difficulty in children with EA. Any
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respiratory symptom during feeding, including tachypnea, wheezing, and cough may
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compromise feeding especially in infants26–28.
Finally, EA patients may develop a fear of eating or texture aversions related to a history of
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food impaction29.
All these mechanisms are often associated and contribute to reduced energy intake which
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leads to under-nutrition and growth failure.
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The prevalence and how to explore digestive, motility and nutritional problems in
GER
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patients with EA (Table 2).
GER is frequent in patients with EA, especially in isolated forms, where it is reported in almost all the patients and often requires fundoplication30. Depending on age, patient selection and diagnostic methods, the prevalence of GER in patients with EA varies from 20% to 63%4,6,10,17,31–45. GER can persist lifelong. Complications such as late or recurrent anastomotic stenosis, esophagitis and Barrett’s Esophagus (BE) can be observed during childhood, adolescence and adulthood (Table 3). There are few longitudinal studies of the natural history of GER in the EA population, and as a result the risk of recurrence of GER has not been accurately assessed. GER appears to be particularly frequent during the first months of life, but especially within the first 5 years in type C EA patients [the most
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common type of TEF] (Table 4). Koivusalo longitudinally assessed GER with esophageal pH-metry and histology in 61 children and showed that the prevalence of GER increased gradually from 16% at age 6 months to 51% at age of 5 years, while 44% of children still had GER at the age of 10 years41. Nonetheless, after 3 years of age, new cases of GER are rare and most of the patients presenting with GER are symptomatic41 .
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24 hour esophageal pH-metry remains the gold standard for the diagnosis of GER46. Koivusalo et al. suggested that early esophageal pH-metry (i.e before the age of 6 months) has a good specificity and positive predictive value for the outcome of EA associated GER
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but is not a good predictor of unfavorable GER or need for anti-reflux surgery38. Specific normal values for esophageal pH-metry are not available in EA patients, but reflux index,
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total number of reflux periods with pH<4 and numbers of periods of pH<4 lasting more than 5 minutes are very similar in EA patients to those in normal infants of the same
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age47,48. A systematic esophageal pH-metry screening for GER by 9-12 months of age is
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recommended.
Esophageal pH-impedance monitoring is a more recent technique that presents advantages compared to isolated esophageal pH-metry. It allows the evaluation of
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retrograde bolus movements in the esophagus independent of the pH, identifying non acidic reflux also in the postprandial period and in patients receiving acid-suppressing
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therapy. It is a dynamic technique and, therefore, can detect the direction of the flow, so that reflux can be distinguished from swallowed oropharyngeal contents. Moreover, it can
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accurately determine the height of the reflux and reflux-related symptoms. Combined with pH monitoring, it can distinguish between acidic and non-acidic reflux episodes10. However, the technique still has limitations: high cost, limited added value regarding therapeutic implications, and lack of evidence-based parameters for the assessment of gastroesophageal reflux and symptom association in children49. Experience of esophageal pH-impedancemetry is increasing in EA patients9,10,17,44,50,51 and has demonstrated that reflux events are mainly non acidic (62.7% of reflux episodes), and that mean acid clearing time and mean bolus clearing time were significantly longer in EA patients compared to controls, adding to the understanding of the pathophysiology of GER in this population9,10,50. On rare occasions, such as in infants presenting with dying/cyanotic spells or those found to have a direct time-related event with non-acidic reflux (using a score), pH-impedancemetry can be helpful when considering the indication for fundoplication. Thus, it is a convenient technique in research for the evaluation of new
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drugs and for the study of swallowing abnormalities9,10,51.
There are no studies assessing the benefit of routine upper gastrointestinal endoscopy in the follow-up of patients with EA. Eighty percent of grade C or D EA patients present with either moderate or severe esophagitis or gastric metaplasia at any time in follow-up, but the risk of occurrence is maximal during the first 3 to 5 years of life. The risk of having
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unfavorable histology after 6 years of repeated normal biopsies is very low42,43. Endoscopic esophageal mucosal abnormalities can be observed in patients with EA
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despite the absence of symptoms.
When performed, upper gastrointestinal endoscopy should carefully examine the upper
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part of the esophagus (inlet patch is more frequent in this population52), esogastric junction and anastomosis area. In addition, the endoscopist should look for stenosis, a diverticulum
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or fistula, hiatal hernia, and peptic or eosinophilic esophagitis. In any case, when an endoscopy is performed and even when it appears macroscopically normal, at least 4
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biopsies, in quadrants, one centimeter above the Z line and one biopsy in the middle part of the esophagus are recommended for Barrett and eosinophilic esophagitis screening. The number of biopsies should be increased in the presence of macroscopic
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abnormalities. GER can remain asymptomatic, and several studies have shown the absence of correlation between clinical signs and complications of GER (mainly
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esophagitis) in this population17,35,36,42,43.
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In children who underwent a fundoplication, repeated systematic endoscopy is recommended, as recurrence of GER and peptic esophagitis or Barrett’s Esophagus are possible for these patients25,30,53.
Anastomotic stricture
AS is the most frequent post-operative complication occurring in 18% to 60% of patients with EA18,54–57. Clinical signs include dysphagia, vomiting, cough, recurrent respiratory infections and poor weight gain56,58 . A history of an esophageal foreign body in a young child with EA [usually retained food such as chicken] is highly suggestive of an AS.
AS is diagnosed by a contrast X-ray or endoscopy. Although no consensus definition of AS exists, it is defined by a reduction of esophageal diameter compared to an age-related
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normal esophagus with associated symptoms. Stricture index (SI) can be calculated with the formula SI= (D-d)/D, in which “D” is the largest diameter of the esophagus closed from the stricture and “d” is the stricture diameter. SI has been used to assess the degree of the stricture at contrast X-Ray59,60 or at endoscopy61. Routine screening for anastomotic stenosis has been advocated by some authors starting 1 month after surgery59,62, while the
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majority recommend to wait for clinical signs suggesting of esophageal stenosis54,56,57.
Dysmotility
Dysphagia is a common complaint occurring in 22-48% of older children and adults with Esophageal motility can be assessed by a contrast study, esophageal
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EA11,36,63.
manometry (water perfused or more recently high resolution) or video manometry. All
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studies suggested one can ascertain the degree of dysmotility; rating it as mild, moderate or severe esophageal dysmotility64. With manometry, the patterns of esophageal
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dysmotility include 3 types: pressurization 15%, distal contraction 50% and aperistalsis 35%. Consistently, the pattern of esophageal dysmotility is not predictive of the presence
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or severity of dysphagia65 nor the outcome of fundoplication. There is currently no evidence for the benefit of using esophageal manometry to direct medical management.
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An upper gastro intestinal contrast study is predictive of delayed esophageal emptying and dysmotility. When performed, an upper gastrointestinal contrast series allows for early
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Nutritional problems
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detection of dysmotility, and can differentiate degrees of severity31.
The reported rates of feeding abnormalities varies from 6% to 11%24,29,66 . After solid food introduction in the diet, the following food difficulties have been observed: slow to feed (52%), cough or choking with feeds (32%), vomiting with feeds (16%)67, food refusal (16%) or dysphagia (61%)4. Children with EA have a significant reduction of height and weight (mean height z score -1.78±1.7) and mean weight for height (-1.1±0.9). Only 7% of patients with EA are less than the 5th percentile for height and weight and low birth weight is predictor of a smaller size37. Initial evaluation of dysphagia includes an endoscopy to evaluate the anastomotic site and esophageal inflammation contributing to symptoms. There is a poor correlation with the symptom of dysphagia and inflammation. It has been reported that 38% of patients with normal esophageal biopsies have food impactions and only 32% of patients with endoscopic inflammation have food impactions42.
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Treatment and follow-up GER GER is frequent during infancy and complications due to GER are observed mostly during the first 2 years of life42. Most of the complications due to GER in EA are linked to acid
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reflux (ie esophagitis, refusal to eat, anastomotic stenosis) rather than non-acidic reflux. Medical management of GER by whatever the agent used (mainly proton pump inhibitor
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(PPI) and H2 receptor antagonists) is successful by reducing gastro-intestinal symptoms, respiratory symptoms or showing an improved weight gain68. There are no efficient pro-
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kinetics currently available.
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There is no evidence to justify increasing systematically the dosage of PPI in EA: neither evidence of abnormal high acidic secretion in this condition, nor resistance to PPI
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reported.
Esophagitis seems more frequent in EA patients and is the leading cause of Barrett’s
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Esophagus, which is a premalignant lesion that can be prevented by PPI69. Long-term treatment with PPI might expose the patient to adverse events although this has been poorly studied in children. Long term PPI treatment is not generally recommended in the
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pediatric population. Therefore, the benefit/risk of long term PPI treatment should be
basis.
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balanced in this population and the need for prolonged treatment reassessed on a regular
Indications for fundoplication vary widely from one center to another. Cumulative risk to have a fundoplication performed in EA patients is up to 45%. In the literature, indications may include failure of maximum conservative therapy for GER and/or esophagitis, an apparent life-threatening event, recurrent anastomotic stenosis, fistula recanalization and failure to thrive37,68,70. In long gap EA, GER seems particularly frequent and is associated with a higher risk of anastomotic stenosis, suggesting that fundoplication should be proposed for a large proportion of those children. The timing of fundoplication varies from one center to another but is often performed during early childhood, between 1 and 24 months after the atresia repair70. However, performing a fundoplication early in life exposes the child to a higher risk of failure71.
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In highly selected cases, when severe reflux persists despite fundoplication, or after repair of a tracheoesophageal cleft, or in severe microgastry, total gastric dissociation could be considered72. However, long term complications including dumping syndrome, nutritional deficiency and growth failure, long term dependency to enteral feeding, Barrett’s
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Esophagus and esophago-jejunal anastomosis stenosis have been recently reported73,74.
Due to the high frequency of GER in infancy and risk of complication, there is a general recommendation to systematically treat all EA patients with PPI during the first months of
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life. An esophageal pH-metry after stopping PPI is recommended at that time. Long-term
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regular endoscopic follow-up of EA patients is also recommended.
Anastomotic stricture
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Conservative treatment consists of intraluminal dilations, to obtain a stable esophageal diameter that allows a normal nutrition and disappearance of symptoms. Dilatations can be done either using semi-rigid dilators (as Savary-Giliard bougies) or balloons. There is no
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consensus about the optimal diameter and frequency of the dilatations59,75. Dilatation sessions are usually repeated every 1 to 2 weeks until a stable diameter is obtained59,75 or
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resolution of the symptoms is achieved54,61. Anastomotic stricture (AS) resection and reanastomosis or partial or total esophageal substitution is reserved for conservative
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management failures.
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Recurrent AS is defined as reappearance of symptoms, 3 or more times, more than 30 days after last dilation75. Experimental data as well as clinical experience suggest that GER is the major cause of recurrent anastomotic stenosis76,77 and in these cases fundoplication has to be considered18. Recurrent AS can also be treated by steroid stricture injection78–81, topical application of the anti-fibroblastic agent mitomycine C82 (Figure 1) and stents83–86.
Dysmotility Intrinsic abnormal motility of the esophagus is a constant feature in EA where pro-kinetics are unlikely to be as efficient as in a child with normal esophageal motility87. Therefore, due to their potential side effects and lack of efficiency, the use of pro-kinetics is not
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recommended in EA patients. There is no current specific drug option to treat dysmotility.
Nutritional problems Aggressive pulmonary toileting, early treatment of infections, and use of inhaled medications are all critical to maintain lung health and reduce the risk of feeding difficulties.
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Careful nutritional follow-up is required and relies on growth and height charts. Several measures can be combined to prevent or treat under-nutrition: individually adapted food consistency and timing of introducing solid foods, oral rehabilitation with help of a speech
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therapist and psychologist, nutritional complements, even enteral nutrition via a
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gastrostomy or via a naso-gastric tube.
Special focus on long gap EA
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Long-gap (LG) EA is a high-risk group for digestive and nutritional problems. LG represents 10% to 26% of the total esophageal atresia (EA) patients –according to its
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definition- mainly observed in type A (pure EA >50%) but also in other forms (type B, C and D). It is a major surgical challenge. Options for esophageal reconstruction include the use of native esophagus –which is the preferred strategy- or esophageal replacement with
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stomach, colon, or small intestine. Besides surgical difficulties, digestive and nutritional problems appear much more frequent than in other forms of EA and are responsible for a
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high morbidity. These problems result from the combination of several factors: EA per se (gastric and esophageal dysmotility, GER), anatomical form (microgastria), and surgery
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(lack of oral feeding due to delayed anastomosis, anastomotic tension, anastomotic stenosis, GER, consequences of esophageal replacement).
Several factors contribute to the physiopathology of GER in long gap EA. Excessive tension at the esophageal anastomosis is associated with a higher incidence of GER. Compared to non-long gap population, the need of repeated dilations (up to 50%), fundoplication (20 to 44 %, often performed very early in life), as well as gastrostomy (almost 100%), and malnutrition (33%) are much more frequent in long gap EA. Microgastria, when severe, often represents an additional challenging problem for gastrostomy feeding (feeding intolerance, leakage around the stoma, dumping syndrome) and need for fundoplication.
Although there are no randomized studies comparing esophageal end to end anastomosis
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to gastro/coloplasty, and the published series are small and retrospective, it has been suggested a higher risk of recurrent esophageal stenosis in end to end anastomosis, similar rate of GERD but more under-nutrition is observed in the long term following gastro/coloplasty. The long gap population is a small but high-risk group for prolonged digestive and nutritional problems. These patients require a prolonged multidisciplinary
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follow-up and should be referred to reference centers.
Future directions for clinical research
To assess natural story of gastro-esophageal reflux with pH-impedancemetry.
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To assess Barrett esophagus and esophageal carcinoma in children and adults with esophageal atresia.
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To asses the prognostic value of high definition manometry in esophageal atresia.
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To test new prokinetics in the management of dysphagia.
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Legends
Mechanisms of gastro esophageal reflux in esophageal atresia
Table 2
Frequency and age of complications of esophageal atresia
Table 3
Complications of gastro esophageal reflux over time
Figure 1
Left: Recurrent anastomotic stenosis in a 15 months old patient with
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Table 1
esophageal atresia (arrow) Right: Upper GI series 3 years after one application of mitomycine C showing the absence of stenosis.
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Table 1 Causes
Mechanisms
Excessive tension at the
-
esophageal anastomosis
References
Decrease
in
lower
sphincter tone -
Shortening
(Yanchar
6,7
2001,
Montedonico 1999)
of
the
intra-abdominal -
Deformity
of
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esophageal segment the
cardioesophageal
Abnormal
esophageal
-
of
esophageal
Wijk
clearance Longer
2013,
Catalano
2011)
acid
and
an
-
(Kawahara 2007, Van
8–10
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motility
Reduction
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junction
bolus clearing times Transient
lower
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-
esophageal sphincter relaxation gastric
emptying
Congenital
-
Surgically
(Jolley 1980, Lopes
5,11–13
induced 2007, Romeo 2000, vagal nerve injury Montgomery 1998)
pt
(controversial)
-
ed
Slow
(Yagi 1997, Bokay
Disturbed
12,14,15
myoelectrical activity (minor
neuromuscular
2005, Romeo 2000)
role)
function,
gastric
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Abnormal
Gastrostomy aggravating
(controversial)
as
an
-
-
Antral hypomotility
-
Gastrostomy
role
can
worsen GER -
(Black 1991, Shah
16,17
2015)
Long-gap EA worsens GER and
-
Long-gap
EA often
necessitate gastrostomy (selection bias)
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Table 2
Frequency
Age
- GER
- 20-63%
- 1-10 years
- Peptic esophagitis
- 9-53%
- 3-5 years
- Barrett esophagus
- 1-2%
- Adolescence, adulthood
- Dysphagia
- 61%
- 5 years
- Anastomotic stricture
- 18-60%
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Complications
- 1 year
-Growth retardation, under- - 30%
- 5 years
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an
nutrition
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Table 3
Time of occurrence
Complication
Frequency
Short term
Laryngomalacia
18-60%
Peptic esophagitis
9-53%
Feeding difficulties
6-11%
Recurrent
anastomotic 6%
Bronchial hyperreactivity Barrett esophagus Esophageal
5-36%
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Long term
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stenosis
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Middle term
Anastomotic stenosis
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aggravation
(3 cases reported)
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adenocarcinoma
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Figure 1
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4. Legrand, C. et al. Long-term outcome of children with oesophageal atresia type III. Arch. Dis. Child. 97, 808–11 (2012).
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5. Jolley, S. G. et al. Patterns of gastroesophageal reflux in children following repair of esophageal atresia and distal tracheoesophageal fistula. J. Pediatr. Surg. 15, 857– 62 (1980).
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6. Yanchar, N. L., Gordon, R., Cooper, M., Dunlap, H. & Soucy, P. Significance of the clinical course and early upper gastrointestinal studies in predicting complications associated with repair of esophageal atresia. J. Pediatr. Surg. 36, 815–22 (2001).
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7. Montedonico, S., Diez-Pardo, J. A., Possögel, A. K. & Tovar, J. A. Effects of esophageal shortening on the gastroesophageal barrier: an experimental study on the causes of reflux in esophageal atresia. J. Pediatr. Surg. 34, 300–3 (1999).
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8. Kawahara, H. et al. Lack of distal esophageal contractions is a key determinant of gastroesophageal reflux disease after repair of esophageal atresia. J. Pediatr. Surg. 42, 2017–21 (2007).
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9. Van Wijk, M., Knüppe, F., Omari, T., de Jong, J. & Benninga, M. Evaluation of gastroesophageal function and mechanisms underlying gastroesophageal reflux in infants and adults born with esophageal atresia. J. Pediatr. Surg. 48, 2496–505 (2013). 10. Catalano, P., Di Pace, M. R., Caruso, A. M., Casuccio, A. & De Grazia, E. Gastroesophageal reflux in young children treated for esophageal atresia: evaluation with pH-multichannel intraluminal impedance. J. Pediatr. Gastroenterol. Nutr. 52, 686–90 (2011). 11. Lopes, M. F. & Botelho, M. F. Midterm follow-up of esophageal anastomosis for esophageal atresia repair: long-gap versus non-long-gap. Dis. Esophagus 20, 428– 35 (2007). 12. Romeo, C. et al. Gastric motility disorders in patients operated on for esophageal atresia and tracheoesophageal fistula: long-term evaluation. J. Pediatr. Surg. 35, 740–4 (2000). 13. Montgomery, M., Escobar-Billing, R., Hellström, P. M., Karlsson, K. A. & Frenckner, B. Impaired gastric emptying in children with repaired esophageal atresia: a controlled study. J. Pediatr. Surg. 33, 476–80 (1998).
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20. Boleken, M. et al. Reduced neuronal innervation in the distal end of the proximal esophageal atretic segment in cases of esophageal atresia with distal tracheoesophageal fistula. World J. Surg. 31, 1512–7 (2007).
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21. Nakazato, Y., Landing, B. H. & Wells, T. R. Abnormal Auerbach plexus in the esophagus and stomach of patients with esophageal atresia and tracheoesophageal fistula. J. Pediatr. Surg. 21, 831–7 (1986).
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24. Koivusalo, A. I., Pakarinen, M. P. & Rintala, R. J. Modern outcomes of oesophageal atresia: single centre experience over the last twenty years. J. Pediatr. Surg. 48, 297–303 (2013). 25. Holschneider, P., Dübbers, M., Engelskirchen, R., Trompelt, J. & Holschneider, A. M. Results of the operative treatment of gastroesophageal reflux in childhood with particular focus on patients with esophageal atresia. Eur. J. Pediatr. Surg. 17, 163– 75 (2007). 26. Smith, I. J. & Beck, J. Mechanical feeding difficulties after primary repair of oesophageal atresia. Acta Paediatr. Scand. 74, 237–9 (1985). 27. Khoshoo, V. & Edell, D. Previously healthy infants may have increased risk of aspiration during respiratory syncytial viral bronchiolitis. Pediatrics 104, 1389–90 (1999). 28. Khoshoo, V., Ross, G., Kelly, B., Edell, D. & Brown, S. Benefits of thickened feeds in previously healthy infants with respiratory syncytial viral bronchiolitis. Pediatr. Page 17 of 22
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32. Engum, S. A., Grosfeld, J. L., West, K. W., Rescorla, F. J. & Scherer, L. R. Analysis of morbidity and mortality in 227 cases of esophageal atresia and/or tracheoesophageal fistula over two decades. Arch. Surg. 130, 502–8; discussion 508–9 (1995).
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33. Chetcuti, P., Myers, N. A., Phelan, P. D. & Beasley, S. W. Adults who survived repair of congenital oesophageal atresia and tracheo-oesophageal fistula. BMJ 297, 344–6 (1988).
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34. Somppi, E. et al. Outcome of patients operated on for esophageal atresia: 30 years’ experience. J. Pediatr. Surg. 33, 1341–6 (1998).
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35. Krug, E. et al. Gastroesophageal reflux and Barrett’s esophagus in adults born with esophageal atresia. Am. J. Gastroenterol. 94, 2825–8 (1999).
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36. Deurloo, J. A. et al. Gastroesophageal reflux: prevalence in adults older than 28 years after correction of esophageal atresia. Ann. Surg. 238, 686–9 (2003).
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37. Deurloo, J. A., Ekkelkamp, S., Schoorl, M., Heij, H. A. & Aronson, D. C. Esophageal atresia: historical evolution of management and results in 371 patients. Ann. Thorac. Surg. 73, 267–72 (2002).
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38. Koivusalo, A., Pakarinen, M., Rintala, R. J. & Lindahl, H. Does postoperative pH monitoring predict complicated gastroesophageal reflux in patients with esophageal atresia? Pediatr. Surg. Int. 20, 670–4 (2004). 39. Konkin, D. E., O’hali, W. A., Webber, E. M. & Blair, G. K. Outcomes in esophageal atresia and tracheoesophageal fistula. J. Pediatr. Surg. 38, 1726–9 (2003). 40. Taylor, A. C. F. et al. Gastroesophageal reflux and related pathology in adults who were born with esophageal atresia: a long-term follow-up study. Clin. Gastroenterol. Hepatol. 5, 702–6 (2007). 41. Koivusalo, A., Pakarinen, M. P. & Rintala, R. J. The cumulative incidence of significant gastrooesophageal reflux in patients with oesophageal atresia with a distal fistula--a systematic clinical, pH-metric, and endoscopic follow-up study. J. Pediatr. Surg. 42, 370–4 (2007). 42. Castilloux, J., Bouron-Dal Soglio, D. & Faure, C. Endoscopic assessment of children with esophageal atresia: Lack of relationship of esophagitis and esophageal metaplasia to symptomatology. Can. J. Gastroenterol. 24, 312–6 (2010). Page 18 of 22
43. Sistonen, S. J., Pakarinen, M. P. & Rintala, R. J. Long-term results of esophageal atresia: Helsinki experience and review of literature. Pediatr. Surg. Int. 27, 1141–9 (2011). 44. Pedersen, R. N. et al. Esophageal atresia: gastroesophageal functional follow-up in 515 year old children. J. Pediatr. Surg. 48, 2487–95 (2013). 45. Bouguermouh, D. & Salem, A. Esophageal atresia: a critical review of management at a single center in Algeria. Dis. Esophagus 28, 205–10 (2015).
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46. Vandenplas, Y. et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, a. J. Pediatr. Gastroenterol. Nutr. 49, 498–547 (2009).
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47. Bergmeijer, J. H., Bouquet, J. & Hazebroek, F. W. Normal ranges of 24-hour pH-metry established in corrected esophageal atresia. J. Pediatr. Gastroenterol. Nutr. 28, 162– 3 (1999).
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48. Vandenplas, Y. & Sacré-Smits, L. Continuous 24-hour esophageal pH monitoring in 285 asymptomatic infants 0-15 months old. J. Pediatr. Gastroenterol. Nutr. 6, 220–4 (1987).
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49. Wenzl, T. G., Benninga, M. A., Loots, C. M., Salvatore, S. & Vandenplas, Y. Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. J. Pediatr. Gastroenterol. Nutr. 55, 230–4 (2012).
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50. Di Pace, M. R. et al. Evaluation of esophageal motility and reflux in children treated for esophageal atresia with the use of combined multichannel intraluminal impedance and pH monitoring. J. Pediatr. Surg. 46, 443–51 (2011).
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51. Fröhlich, T. et al. Combined esophageal multichannel intraluminal impedance and pH monitoring after repair of esophageal atresia. J. Pediatr. Gastroenterol. Nutr. 47, 443–9 (2008). 52. Georges, A. et al. Inlet Patch: Clinical Presentation and Outcome in Children. J. Pediatr. Gastroenterol. Nutr. 52, 419–423 (2011). 53. Lindahl, H., Rintala, R. & Louhimo, I. Failure of the Nissen fundoplication to control gastroesophageal reflux in esophageal atresia patients. J. Pediatr. Surg. 24, 985–7 (1989). 54. Michaud, L. et al. [Anastomotic stenosis after surgical treatment of esophageal atresia: frequency, risk factors and effectiveness of esophageal dilatations]. Arch. Pediatr. 8, 268–74 (2001). 55. Kovesi, T. & Rubin, S. Long-term complications of congenital esophageal atresia and/or tracheoesophageal fistula. Chest 126, 915–25 (2004).
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56. Spitz, L. Esophageal atresia. J. Pediatr. Surg. 41, 1635–1640 (2006). 57. Serhal, L. et al. Anastomotic stricture after surgical repair of esophageal atresia: frequency, risk factors, and efficacy of esophageal bougie dilatations. J. Pediatr. Surg. 45, 1459–62 (2010). 58. Gatzinsky, V., Jönsson, L., Ekerljung, L., Friberg, L.-G. & Wennergren, G. Long-term respiratory symptoms following oesophageal atresia. Acta Paediatr. 100, 1222–5 (2011).
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59. Said, M. et al. Balloon dilatation of anastomotic strictures secondary to surgical repair of oesophageal atresia. Br. J. Radiol. 76, 26–31 (2003).
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60. Zhao, R., Li, K., Shen, C. & Zheng, S. The outcome of conservative treatment for anastomotic leakage after surgical repair of esophageal atresia. J. Pediatr. Surg. 46, 2274–8 (2011). 61. Parolini, F. et al. Anastomotic strictures and endoscopic dilatations following esophageal atresia repair. Pediatr. Surg. Int. 29, 601–5 (2013).
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62. Hagander, L., Muszynska, C., Arnbjornsson, E. & Sandgren, K. Prophylactic treatment with proton pump inhibitors in children operated on for oesophageal atresia. Eur. J. Pediatr. Surg. 22, 139–42 (2012). 63. Little, D. C. et al. Long-term analysis of children with esophageal atresia and tracheoesophageal fistula. J. Pediatr. Surg. 38, 852–6 (2003).
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64. Deurloo, J. A., Klinkenberg, E. C., Ekkelkamp, S., Heij, H. A. & Aronson, D. C. Adults with corrected oesophageal atresia: is oesophageal function associated with complaints and/or quality of life? Pediatr. Surg. Int. 24, 537–41 (2008).
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65. Lemoine, C. et al. Characterization of esophageal motility following esophageal atresia repair using high-resolution esophageal manometry. J. Pediatr. Gastroenterol. Nutr. 56, 609–14 (2013). 66. Baird, R., Levesque, D., Birnbaum, R. & Ramsay, M. A pilot investigation of feeding problems in children with esophageal atresia. Dis. Esophagus 28, 224–8 (2015). 67. Puntis, J. W., Ritson, D. G., Holden, C. E. & Buick, R. G. Growth and feeding problems after repair of oesophageal atresia. Arch. Dis. Child. 65, 84–8 (1990). 68. Shawyer, A. C., D’Souza, J., Pemberton, J. & Flageole, H. The management of postoperative reflux in congenital esophageal atresia–tracheoesophageal fistula: a systematic review. Pediatr. Surg. Int. 30, 987–996 (2014). 69. Schneider, A., Michaud, L. & Gottrand, F. Esophageal atresia: metaplasia, Barrett. Dis. Esophagus 26, 425–427 (2013). 70. Bergmeijer, J. H., Tibboel, D. & Hazebroek, F. W. Nissen fundoplication in the management of gastroesophageal reflux occurring after repair of esophageal atresia. J. Pediatr. Surg. 35, 573–6 (2000).
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71. Lopez-Fernandez, S. et al. Failed Nissen fundoplication in children: causes and management. Eur. J. Pediatr. Surg. 24, 79–82 (2014). 72. De Lagausie, P. et al. Reflux in esophageal atresia, tracheoesophageal cleft, and esophagocoloplasty: Bianchi’s procedure as an alternative approach. J. Pediatr. Surg. 40, 666–9 (2005).
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73. Gottrand, M. et al. Barrett esophagus and esophagojejunal anastomotic stenosis as complications of esophagogastric disconnection in children with esophageal atresia. J. Pediatr. Gastroenterol. Nutr. 57, 93–5 (2013).
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74. Madre, C. et al. Prolonged enteral feeding is often required to avoid long-term nutritional and metabolic complications after esophagogastric dissociation. J. Pediatr. Gastroenterol. Nutr. 50, 280–6 (2010).
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75. Antoniou, D., Soutis, M. & Christopoulos-Geroulanos, G. Anastomotic strictures following esophageal atresia repair: a 20-year experience with endoscopic balloon dilatation. J. Pediatr. Gastroenterol. Nutr. 51, 464–7 (2010).
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76. Banjar, H. H. & Al-Nassar, S. I. Gastroesophageal reflux following repair of esophageal atresia and tracheoesophageal fistula. Saudi Med. J. 26, 781–5 (2005).
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77. McKinnon, L. J. & Kosloske, A. M. Prediction and prevention of anastomotic complications of esophageal atresia and tracheoesophageal fistula. J. Pediatr. Surg. 25, 778–81 (1990).
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78. Lilly, J. R. & Bensard, D. Intralesional steroid injection in the management of esophageal stricture. J. Pediatr. Surg. 24, 1312 (1989).
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79. Gandhi, R. P., Cooper, A. & Barlow, B. A. Successful management of esophageal strictures without resection or replacement. J. Pediatr. Surg. 24, 745–9; discussion 749–50 (1989).
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80. Zein, N. N., Greseth, J. M. & Perrault, J. Endoscopic intralesional steroid injections in the management of refractory esophageal strictures. Gastrointest. Endosc. 41, 596– 8 (1995). 81. Hirdes, M. M. C. et al. Endoscopic corticosteroid injections do not reduce dysphagia after endoscopic dilation therapy in patients with benign esophagogastric anastomotic strictures. Clin. Gastroenterol. Hepatol. 11, 795–801.e1 (2013). 82. Uhlen, S. et al. Mitomycin C: an alternative conservative treatment for refractory esophageal stricture in children? Endoscopy 38, 404–7 (2006). 83. Kramer, R. E. & Quiros, J. A. Esophageal stents for severe strictures in young children: experience, benefits, and risk. Curr. Gastroenterol. Rep. 12, 203–10 (2010). 84. Broto, J., Asensio, M. & Vernet, J. M. G. Results of a new technique in the treatment of severe esophageal stenosis in children: poliflex stents. J. Pediatr. Gastroenterol. Nutr. 37, 203–6 (2003). 85. Manfredi, M. A. et al. Externally removable stents in the treatment of benign Page 21 of 22
recalcitrant strictures and esophageal perforations in pediatric patients with esophageal atresia. Gastrointest. Endosc. 80, 246–52 (2014). 86. Caldaro, T. et al. Dynamic esophageal stents. Dis. Esophagus 26, 388–91 (2013).
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87. Tovar, J. A. et al. Ambulatory 24-hour manometric and pH metric evidence of permanent impairment of clearance capacity in patients with esophageal atresia. J. Pediatr. Surg. 30, 1224–31 (1995).
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S1526-0542(15)00142-6 http://dx.doi.org/doi:10.1016/j.prrv.2015.11.005 YPRRV 1103
To appear in:
YPRRV
Received date: Accepted date:
14-10-2015 16-11-2015
Please cite this article as: Gottrand M, Michaud L, Sfeir R, Gottrand F, Motility, digestive and nutritional problems in Esophageal Atresia, Paediatric Respiratory Reviews (2015), http://dx.doi.org/10.1016/j.prrv.2015.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Motility, digestive and nutritional problems in Esophageal Atresia Madeleine Gottrand, Laurent Michaud, Rony Sfeir, Frederic Gottrand
esophagus, Department of Pediatrics, F-59000 Lille, France
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CHU Lille, Univ. Lille, National reference center for congenital malformation of the
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[email protected], [email protected], [email protected]
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Corresponding author: Frederic Gottrand, [email protected]
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Tel : +333 20 44 61 26, Fax + 333 20 44 61 34
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Conflicts of interest: None
Page 1 of 22
Summary Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a rare congenital malformation. Digestive and nutritional problems remain frequent in children with EA both in early infancy and at long-term follow-up. These patients are at major risk of presenting with gastroesophageal reflux and its complications, such as anastomotic
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strictures. Esophageal dysmotility is constant, and can have important consequences on feeding and nutritional status. Patients with EA need a systematic follow-up with a
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multidisciplinary team.
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Key words Anastomotic stricture Growth Retardation
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Dysphagia Gastro-Esophageal Reflux
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Dysmotility Nutrition
Educational Aims
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Children
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The reader will come to appreciate that:
Digestive and nutritional problems are frequent and interlinked in esophageal
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atresia.
A multidisciplinary approach is needed in esophageal atresia. Esophageal atresia is not only a surgical neonatal problem but has life-long consequences on the digestive and nutritional morbidity.
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Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a rare congenital malformation1,2. The live-birth prevalence of EA is 1.8 per 10 000 births in France3. The prognosis of EA has benefited from advances in medical care, including neonatal and surgical procedures, and has therefore improved significantly over the past three decades. Its survival rate now exceeds 95% and an increasing number of patients reach adulthood2,3. However, digestive/nutritional problems remain frequent in this
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population both in early infancy and at long-term follow-up4.
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Why are digestive, motility and nutritional problems a concern in patients with EA? Gastro-esophageal reflux (GER)
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Patients with EA are at major risk of presenting GER5. Several factors contribute to
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the physiopathology of GER in EA (Table 1).
Anastomotic stricture
Anastomotic stricture (AS) is favoured by important anastomotic tension related to a long-
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gap between the two esophageal pouches, occurrence of a post-operative anastomotic
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leak and GER18.
Dysmotility
Dysmotility is not only a consequence of surgical repair as abnormal innervation is
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present at birth. It involves the Auerbach plexus, ganglion cells, interstitial cells of Cajal (ICC), and both excitatory and inhibitory intramural nerves mostly in the distal esophageal
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segment rather than in the proximal esophagus19–22. Dysmotility is explained by an imbalance of neurotransmitter excretion in nerve cells with decreased expression of neuronal markers, including vasoactive intestinal polypeptide (VIP) and nitric oxide synthase (NOS)19,20.These congenital changes in the innervation may lead to abnormal contraction and relaxation and subsequent dysphagia, GER, and feeding difficulty in children with EA23.
Nutritional problems Dysphagia is one of the main causes of nutritional problems. Causes of dysphagia include esophagitis, GER, eosinophilic esophagitis, dysmotility, anastomotic strictures, esophageal outlet obstruction, aspiration and fear of feeding. Predictors of poor oral intake
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are long gap atresia, CHARGE association, and neurologic abnormalities24. GER and esophagitis have been implicated as causes of feeding difficulties. However, motility abnormalities may contribute to a much greater extent to dysphagia.Anastomotic strictures are another frequent cause of dysphagia and feeding difficulties.
Fundoplication, which can create a functional esophageal outlet obstruction in the context
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of dysmotility, may also cause or aggravate dysphagia and feeding difficulties. This is supported by a study of children receiving a fundoplication, where 4.3% of the cohort
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without EA presented with dysphagia, versus 17% in children with EA25.
Aspiration is an under-recognized cause of feeding difficulty in children with EA. Any
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respiratory symptom during feeding, including tachypnea, wheezing, and cough may
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compromise feeding especially in infants26–28.
Finally, EA patients may develop a fear of eating or texture aversions related to a history of
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food impaction29.
All these mechanisms are often associated and contribute to reduced energy intake which
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leads to under-nutrition and growth failure.
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The prevalence and how to explore digestive, motility and nutritional problems in
GER
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patients with EA (Table 2).
GER is frequent in patients with EA, especially in isolated forms, where it is reported in almost all the patients and often requires fundoplication30. Depending on age, patient selection and diagnostic methods, the prevalence of GER in patients with EA varies from 20% to 63%4,6,10,17,31–45. GER can persist lifelong. Complications such as late or recurrent anastomotic stenosis, esophagitis and Barrett’s Esophagus (BE) can be observed during childhood, adolescence and adulthood (Table 3). There are few longitudinal studies of the natural history of GER in the EA population, and as a result the risk of recurrence of GER has not been accurately assessed. GER appears to be particularly frequent during the first months of life, but especially within the first 5 years in type C EA patients [the most
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common type of TEF] (Table 4). Koivusalo longitudinally assessed GER with esophageal pH-metry and histology in 61 children and showed that the prevalence of GER increased gradually from 16% at age 6 months to 51% at age of 5 years, while 44% of children still had GER at the age of 10 years41. Nonetheless, after 3 years of age, new cases of GER are rare and most of the patients presenting with GER are symptomatic41 .
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24 hour esophageal pH-metry remains the gold standard for the diagnosis of GER46. Koivusalo et al. suggested that early esophageal pH-metry (i.e before the age of 6 months) has a good specificity and positive predictive value for the outcome of EA associated GER
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but is not a good predictor of unfavorable GER or need for anti-reflux surgery38. Specific normal values for esophageal pH-metry are not available in EA patients, but reflux index,
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total number of reflux periods with pH<4 and numbers of periods of pH<4 lasting more than 5 minutes are very similar in EA patients to those in normal infants of the same
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age47,48. A systematic esophageal pH-metry screening for GER by 9-12 months of age is
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recommended.
Esophageal pH-impedance monitoring is a more recent technique that presents advantages compared to isolated esophageal pH-metry. It allows the evaluation of
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retrograde bolus movements in the esophagus independent of the pH, identifying non acidic reflux also in the postprandial period and in patients receiving acid-suppressing
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therapy. It is a dynamic technique and, therefore, can detect the direction of the flow, so that reflux can be distinguished from swallowed oropharyngeal contents. Moreover, it can
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accurately determine the height of the reflux and reflux-related symptoms. Combined with pH monitoring, it can distinguish between acidic and non-acidic reflux episodes10. However, the technique still has limitations: high cost, limited added value regarding therapeutic implications, and lack of evidence-based parameters for the assessment of gastroesophageal reflux and symptom association in children49. Experience of esophageal pH-impedancemetry is increasing in EA patients9,10,17,44,50,51 and has demonstrated that reflux events are mainly non acidic (62.7% of reflux episodes), and that mean acid clearing time and mean bolus clearing time were significantly longer in EA patients compared to controls, adding to the understanding of the pathophysiology of GER in this population9,10,50. On rare occasions, such as in infants presenting with dying/cyanotic spells or those found to have a direct time-related event with non-acidic reflux (using a score), pH-impedancemetry can be helpful when considering the indication for fundoplication. Thus, it is a convenient technique in research for the evaluation of new
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drugs and for the study of swallowing abnormalities9,10,51.
There are no studies assessing the benefit of routine upper gastrointestinal endoscopy in the follow-up of patients with EA. Eighty percent of grade C or D EA patients present with either moderate or severe esophagitis or gastric metaplasia at any time in follow-up, but the risk of occurrence is maximal during the first 3 to 5 years of life. The risk of having
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unfavorable histology after 6 years of repeated normal biopsies is very low42,43. Endoscopic esophageal mucosal abnormalities can be observed in patients with EA
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despite the absence of symptoms.
When performed, upper gastrointestinal endoscopy should carefully examine the upper
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part of the esophagus (inlet patch is more frequent in this population52), esogastric junction and anastomosis area. In addition, the endoscopist should look for stenosis, a diverticulum
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or fistula, hiatal hernia, and peptic or eosinophilic esophagitis. In any case, when an endoscopy is performed and even when it appears macroscopically normal, at least 4
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biopsies, in quadrants, one centimeter above the Z line and one biopsy in the middle part of the esophagus are recommended for Barrett and eosinophilic esophagitis screening. The number of biopsies should be increased in the presence of macroscopic
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abnormalities. GER can remain asymptomatic, and several studies have shown the absence of correlation between clinical signs and complications of GER (mainly
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esophagitis) in this population17,35,36,42,43.
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In children who underwent a fundoplication, repeated systematic endoscopy is recommended, as recurrence of GER and peptic esophagitis or Barrett’s Esophagus are possible for these patients25,30,53.
Anastomotic stricture
AS is the most frequent post-operative complication occurring in 18% to 60% of patients with EA18,54–57. Clinical signs include dysphagia, vomiting, cough, recurrent respiratory infections and poor weight gain56,58 . A history of an esophageal foreign body in a young child with EA [usually retained food such as chicken] is highly suggestive of an AS.
AS is diagnosed by a contrast X-ray or endoscopy. Although no consensus definition of AS exists, it is defined by a reduction of esophageal diameter compared to an age-related
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normal esophagus with associated symptoms. Stricture index (SI) can be calculated with the formula SI= (D-d)/D, in which “D” is the largest diameter of the esophagus closed from the stricture and “d” is the stricture diameter. SI has been used to assess the degree of the stricture at contrast X-Ray59,60 or at endoscopy61. Routine screening for anastomotic stenosis has been advocated by some authors starting 1 month after surgery59,62, while the
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majority recommend to wait for clinical signs suggesting of esophageal stenosis54,56,57.
Dysmotility
Dysphagia is a common complaint occurring in 22-48% of older children and adults with Esophageal motility can be assessed by a contrast study, esophageal
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EA11,36,63.
manometry (water perfused or more recently high resolution) or video manometry. All
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studies suggested one can ascertain the degree of dysmotility; rating it as mild, moderate or severe esophageal dysmotility64. With manometry, the patterns of esophageal
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dysmotility include 3 types: pressurization 15%, distal contraction 50% and aperistalsis 35%. Consistently, the pattern of esophageal dysmotility is not predictive of the presence
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or severity of dysphagia65 nor the outcome of fundoplication. There is currently no evidence for the benefit of using esophageal manometry to direct medical management.
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An upper gastro intestinal contrast study is predictive of delayed esophageal emptying and dysmotility. When performed, an upper gastrointestinal contrast series allows for early
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Nutritional problems
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detection of dysmotility, and can differentiate degrees of severity31.
The reported rates of feeding abnormalities varies from 6% to 11%24,29,66 . After solid food introduction in the diet, the following food difficulties have been observed: slow to feed (52%), cough or choking with feeds (32%), vomiting with feeds (16%)67, food refusal (16%) or dysphagia (61%)4. Children with EA have a significant reduction of height and weight (mean height z score -1.78±1.7) and mean weight for height (-1.1±0.9). Only 7% of patients with EA are less than the 5th percentile for height and weight and low birth weight is predictor of a smaller size37. Initial evaluation of dysphagia includes an endoscopy to evaluate the anastomotic site and esophageal inflammation contributing to symptoms. There is a poor correlation with the symptom of dysphagia and inflammation. It has been reported that 38% of patients with normal esophageal biopsies have food impactions and only 32% of patients with endoscopic inflammation have food impactions42.
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Treatment and follow-up GER GER is frequent during infancy and complications due to GER are observed mostly during the first 2 years of life42. Most of the complications due to GER in EA are linked to acid
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reflux (ie esophagitis, refusal to eat, anastomotic stenosis) rather than non-acidic reflux. Medical management of GER by whatever the agent used (mainly proton pump inhibitor
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(PPI) and H2 receptor antagonists) is successful by reducing gastro-intestinal symptoms, respiratory symptoms or showing an improved weight gain68. There are no efficient pro-
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kinetics currently available.
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There is no evidence to justify increasing systematically the dosage of PPI in EA: neither evidence of abnormal high acidic secretion in this condition, nor resistance to PPI
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reported.
Esophagitis seems more frequent in EA patients and is the leading cause of Barrett’s
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Esophagus, which is a premalignant lesion that can be prevented by PPI69. Long-term treatment with PPI might expose the patient to adverse events although this has been poorly studied in children. Long term PPI treatment is not generally recommended in the
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pediatric population. Therefore, the benefit/risk of long term PPI treatment should be
basis.
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balanced in this population and the need for prolonged treatment reassessed on a regular
Indications for fundoplication vary widely from one center to another. Cumulative risk to have a fundoplication performed in EA patients is up to 45%. In the literature, indications may include failure of maximum conservative therapy for GER and/or esophagitis, an apparent life-threatening event, recurrent anastomotic stenosis, fistula recanalization and failure to thrive37,68,70. In long gap EA, GER seems particularly frequent and is associated with a higher risk of anastomotic stenosis, suggesting that fundoplication should be proposed for a large proportion of those children. The timing of fundoplication varies from one center to another but is often performed during early childhood, between 1 and 24 months after the atresia repair70. However, performing a fundoplication early in life exposes the child to a higher risk of failure71.
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In highly selected cases, when severe reflux persists despite fundoplication, or after repair of a tracheoesophageal cleft, or in severe microgastry, total gastric dissociation could be considered72. However, long term complications including dumping syndrome, nutritional deficiency and growth failure, long term dependency to enteral feeding, Barrett’s
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Esophagus and esophago-jejunal anastomosis stenosis have been recently reported73,74.
Due to the high frequency of GER in infancy and risk of complication, there is a general recommendation to systematically treat all EA patients with PPI during the first months of
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life. An esophageal pH-metry after stopping PPI is recommended at that time. Long-term
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regular endoscopic follow-up of EA patients is also recommended.
Anastomotic stricture
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Conservative treatment consists of intraluminal dilations, to obtain a stable esophageal diameter that allows a normal nutrition and disappearance of symptoms. Dilatations can be done either using semi-rigid dilators (as Savary-Giliard bougies) or balloons. There is no
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consensus about the optimal diameter and frequency of the dilatations59,75. Dilatation sessions are usually repeated every 1 to 2 weeks until a stable diameter is obtained59,75 or
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resolution of the symptoms is achieved54,61. Anastomotic stricture (AS) resection and reanastomosis or partial or total esophageal substitution is reserved for conservative
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management failures.
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Recurrent AS is defined as reappearance of symptoms, 3 or more times, more than 30 days after last dilation75. Experimental data as well as clinical experience suggest that GER is the major cause of recurrent anastomotic stenosis76,77 and in these cases fundoplication has to be considered18. Recurrent AS can also be treated by steroid stricture injection78–81, topical application of the anti-fibroblastic agent mitomycine C82 (Figure 1) and stents83–86.
Dysmotility Intrinsic abnormal motility of the esophagus is a constant feature in EA where pro-kinetics are unlikely to be as efficient as in a child with normal esophageal motility87. Therefore, due to their potential side effects and lack of efficiency, the use of pro-kinetics is not
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recommended in EA patients. There is no current specific drug option to treat dysmotility.
Nutritional problems Aggressive pulmonary toileting, early treatment of infections, and use of inhaled medications are all critical to maintain lung health and reduce the risk of feeding difficulties.
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Careful nutritional follow-up is required and relies on growth and height charts. Several measures can be combined to prevent or treat under-nutrition: individually adapted food consistency and timing of introducing solid foods, oral rehabilitation with help of a speech
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therapist and psychologist, nutritional complements, even enteral nutrition via a
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gastrostomy or via a naso-gastric tube.
Special focus on long gap EA
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Long-gap (LG) EA is a high-risk group for digestive and nutritional problems. LG represents 10% to 26% of the total esophageal atresia (EA) patients –according to its
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definition- mainly observed in type A (pure EA >50%) but also in other forms (type B, C and D). It is a major surgical challenge. Options for esophageal reconstruction include the use of native esophagus –which is the preferred strategy- or esophageal replacement with
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stomach, colon, or small intestine. Besides surgical difficulties, digestive and nutritional problems appear much more frequent than in other forms of EA and are responsible for a
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high morbidity. These problems result from the combination of several factors: EA per se (gastric and esophageal dysmotility, GER), anatomical form (microgastria), and surgery
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(lack of oral feeding due to delayed anastomosis, anastomotic tension, anastomotic stenosis, GER, consequences of esophageal replacement).
Several factors contribute to the physiopathology of GER in long gap EA. Excessive tension at the esophageal anastomosis is associated with a higher incidence of GER. Compared to non-long gap population, the need of repeated dilations (up to 50%), fundoplication (20 to 44 %, often performed very early in life), as well as gastrostomy (almost 100%), and malnutrition (33%) are much more frequent in long gap EA. Microgastria, when severe, often represents an additional challenging problem for gastrostomy feeding (feeding intolerance, leakage around the stoma, dumping syndrome) and need for fundoplication.
Although there are no randomized studies comparing esophageal end to end anastomosis
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to gastro/coloplasty, and the published series are small and retrospective, it has been suggested a higher risk of recurrent esophageal stenosis in end to end anastomosis, similar rate of GERD but more under-nutrition is observed in the long term following gastro/coloplasty. The long gap population is a small but high-risk group for prolonged digestive and nutritional problems. These patients require a prolonged multidisciplinary
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follow-up and should be referred to reference centers.
Future directions for clinical research
To assess natural story of gastro-esophageal reflux with pH-impedancemetry.
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To assess Barrett esophagus and esophageal carcinoma in children and adults with esophageal atresia.
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To asses the prognostic value of high definition manometry in esophageal atresia.
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To test new prokinetics in the management of dysphagia.
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Legends
Mechanisms of gastro esophageal reflux in esophageal atresia
Table 2
Frequency and age of complications of esophageal atresia
Table 3
Complications of gastro esophageal reflux over time
Figure 1
Left: Recurrent anastomotic stenosis in a 15 months old patient with
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Table 1
esophageal atresia (arrow) Right: Upper GI series 3 years after one application of mitomycine C showing the absence of stenosis.
Page 11 of 22
Table 1 Causes
Mechanisms
Excessive tension at the
-
esophageal anastomosis
References
Decrease
in
lower
sphincter tone -
Shortening
(Yanchar
6,7
2001,
Montedonico 1999)
of
the
intra-abdominal -
Deformity
of
ip t
esophageal segment the
cardioesophageal
Abnormal
esophageal
-
of
esophageal
Wijk
clearance Longer
2013,
Catalano
2011)
acid
and
an
-
(Kawahara 2007, Van
8–10
us
motility
Reduction
cr
junction
bolus clearing times Transient
lower
M
-
esophageal sphincter relaxation gastric
emptying
Congenital
-
Surgically
(Jolley 1980, Lopes
5,11–13
induced 2007, Romeo 2000, vagal nerve injury Montgomery 1998)
pt
(controversial)
-
ed
Slow
(Yagi 1997, Bokay
Disturbed
12,14,15
myoelectrical activity (minor
neuromuscular
2005, Romeo 2000)
role)
function,
gastric
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Abnormal
Gastrostomy aggravating
(controversial)
as
an
-
-
Antral hypomotility
-
Gastrostomy
role
can
worsen GER -
(Black 1991, Shah
16,17
2015)
Long-gap EA worsens GER and
-
Long-gap
EA often
necessitate gastrostomy (selection bias)
Page 12 of 22
Table 2
Frequency
Age
- GER
- 20-63%
- 1-10 years
- Peptic esophagitis
- 9-53%
- 3-5 years
- Barrett esophagus
- 1-2%
- Adolescence, adulthood
- Dysphagia
- 61%
- 5 years
- Anastomotic stricture
- 18-60%
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Complications
- 1 year
-Growth retardation, under- - 30%
- 5 years
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nutrition
Page 13 of 22
Table 3
Time of occurrence
Complication
Frequency
Short term
Laryngomalacia
18-60%
Peptic esophagitis
9-53%
Feeding difficulties
6-11%
Recurrent
anastomotic 6%
Bronchial hyperreactivity Barrett esophagus Esophageal
5-36%
an
Long term
us
stenosis
cr
Middle term
Anastomotic stenosis
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aggravation
(3 cases reported)
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M
adenocarcinoma
Page 14 of 22
Ac ce
pt
ed
M
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Figure 1
Page 15 of 22
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